A Phase 2a Randomized, Parallel Group, Dose-Ranging Study of Molindone in Children with Attention-Deficit/Hyperactivity Disorder and Persistent, Serious Conduct Problems

Objective: To evaluate safety and tolerability of four doses of immediate-release molindone hydrochloride in children with attention-deficit/hyperactivity disorder (ADHD) and serious conduct problems. Methods: This open-label, parallel-group, dose-ranging, multicenter trial randomized children, aged 6-12 years, with ADHD and persistent, serious conduct problems to receive oral molindone thrice daily for 9-12 weeks in four treatment groups: Group 1-10 mg (5 mg if weight < 30 kg), group 2-20 mg (10 mg if < 30 kg), group 3-30 mg (15 mg if < 30 kg), and group 4-40 mg (20 mg if < 30 kg). The primary outcome measure was to evaluate safety and tolerability of molindone in children with ADHD and serious conduct problems. Secondary outcome measures included change in Nisonger Child Behavior Rating Form-Typical Intelligence Quotient (NCBRF-TIQ) Conduct Problem subscale scores, change in Clinical Global Impressions-Severity (CGI-S) and -Improvement (CGI-I) subscale scores from baseline to end point, and Swanson, Nolan, and Pelham rating scale-revised (SNAP-IV) ADHD-related subscale scores. Results: The study randomized 78 children; 55 completed the study. Treatment with molindone was generally well tolerated, with no clinically meaningful changes in laboratory or physical examination findings. The most common treatment-related adverse events (AEs) included somnolence (n = 9), weight increase (n = 8), akathisia (n = 4), sedation (n = 4), and abdominal pain (n = 4). Mean weight increased by 0.54 kg, and mean body mass index by 0.24 kg/m(2). The incidence of AEs and treatment-related AEs increased with increasing dose. NCBRF-TIQ subscale scores improved in all four treatment groups, with 34%, 34%, 32%, and 55% decreases from baseline in groups 1, 2, 3, and 4, respectively. CGI-S and SNAP-IV scores improved over time in all treatment groups, and CGI-I scores improved to the greatest degree in group 4. Conclusions: Molindone at doses of 5-20 mg/day (children weighing < 30 kg) and 20-40 mg ( >= 30 kg) was well tolerated, and preliminary efficacy results suggest that molindone produces dose-related behavioral improvements over 9-12 weeks. Additional double-blind, placebo-controlled trials are needed to further investigate molindone in this pediatric population.